Wang Y, Freund R K, Palmer M R
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
J Pharmacol Exp Ther. 1999 Jan;288(1):211-20.
We previously found that beta adrenergic agonists such as norepinephrine and isoproterenol potentiate the depressant actions of ethanol (EtOH) on cerebellar Purkinje neurons. Furthermore, antagonism of the beta adrenergic effects of endogenously released catecholamines with timolol reduced EtOH-induced depressions of neuronal activity in that brain area. In the present study, we further investigated the hypothesis that activity of the endogenous noradrenergic innervation to the cerebellar cortex can potentiate this EtOH action. We investigated the interaction of synaptically released catecholamines on EtOH-induced depressions of cerebellar Purkinje neurons in three different experiments: (1) endogenous catecholamine release was facilitated by applying the catecholamine uptake inhibitor desmethylimipramine, (2) activity of the noradrenergic innervation of the cerebellar cortex from locus ceruleus was increased by causing acute withdrawal from 7 days of chronic morphine treatment with the opiate antagonist naloxone, and (3) the noradrenergic innervation of the cerebellum was activated directly by electrical stimulation of the locus ceruleus. We found that all three conditions potentiated EtOH-induced depressions in the cerebellum and that this potentiation of ethanol effects could be antagonized by the systemic administration of the beta adrenergic antagonist propranolol. Furthermore, morphine withdrawal also caused potentiation of the depressant effects of phencyclidine, which are known to be regulated by the endogenous catecholamine innervation in this brain area. Taken together with our previous data demonstrating a beta adrenergic facilitation of EtOH actions in this brain area, the present results suggest that the activity of endogenous noradrenergic synapses can regulate the depressant effects of EtOH on cerebellar Purkinje neurons.
我们之前发现，去甲肾上腺素和异丙肾上腺素等β-肾上腺素能激动剂可增强乙醇（EtOH）对小脑浦肯野神经元的抑制作用。此外，用噻吗洛尔拮抗内源性释放的儿茶酚胺的β-肾上腺素能效应，可减轻EtOH诱导的该脑区神经元活动抑制。在本研究中，我们进一步探讨了内源性去甲肾上腺素能神经支配小脑皮质的活动可增强这种EtOH作用的假说。我们在三个不同实验中研究了突触释放的儿茶酚胺对EtOH诱导的小脑浦肯野神经元抑制的相互作用：（1）应用儿茶酚胺摄取抑制剂去甲丙咪嗪促进内源性儿茶酚胺释放；（2）用阿片拮抗剂纳洛酮使小鼠从7天慢性吗啡治疗中急性戒断，以增加蓝斑对小脑皮质的去甲肾上腺素能神经支配活动；（3）直接电刺激蓝斑激活小脑的去甲肾上腺素能神经支配。我们发现，所有这三种情况均增强了EtOH诱导的小脑抑制作用，且这种乙醇效应的增强可被全身给予β-肾上腺素能拮抗剂普萘洛尔所拮抗。此外，吗啡戒断还导致苯环己哌啶抑制作用增强，已知该作用受该脑区内源性儿茶酚胺神经支配调节。结合我们之前的数据表明该脑区中β-肾上腺素能促进EtOH作用，目前的结果表明内源性去甲肾上腺素能突触的活动可调节EtOH对小脑浦肯野神经元的抑制作用。
